This study contributes valuable information to connect functional findings to the clinically important outcome of addiction in humans. Several neurobiological, functional, and physiological changes have been demonstrated for the rs1799971 (A118G) amino acid change and a corresponding mutation in a similar region of the receptor in mice (A112G) (Drakenberg et al. 2006; Huang et al. 2012; Mague and Blendy 2010; Palmer and de Wit 2012; Ray et al. 2012; Wang et al. 2014). In vitro studies of the G allele have reported increased binding to β- endorphin (Bond et al. 1998), altered downstream signaling (Deb et al. 2010), and decreased mu opioid receptor expression (Zhang et al. 2005). In human brain imaging, the G allele is associated with striatal dopamine response to alcohol (Ramchandani et al. 2011) and increased mu opioid receptor binding potential (Ray et al. 2011). In mouse knock-in models (A112G), the G/G knock-in has shown reduced receptor protein levels overall and reduced reinforcing value of morphine in female mice (Mague et al. 2009), reduced G-protein signaling (Wang et al. 2014), and increased peak dopamine response to alcohol challenge (Ramchandani et al. 2011); changes are often brain-region specific.
